Genetics of Listeria induced changes in gene expression

李斯特菌的遗传学引起基因表达的变化

• 批准号: 6873829
• 负责人: Victor L Boyartchuk
• 金额: $ 8.1万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-04-01 至 2007-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6873829
• 关键词: Listeria infections; gene expression; gene expression profiling; gene mutation; genetic mapping; genetic polymorphism; genetic strain; genetic susceptibility; immune response; immunogenetics; intravenous administration; laboratory mouse; polymerase chain reaction

DESCRIPTION (provided by applicant): Mammalian hosts, from inbred mouse strains to humans, display a wide range of phenotypic responses to various bacterial infections. One of the pathogens eliciting such differential responses in mice is Listena monocytogenes, a Gram-positive bacterium which is a common source of food poisoning. Previous studies have established that differences in immune response are often genetically controlled. Differences in immune response can be characterized using a variety of readouts, from gene expression changes to disease outcome. Currently, gene expression data is the most comprehensive way to describe a biological system. In addition, gene expression values can be used directly in genetic quantitative trait mapping experiments. Therefore, by monitoring differential transcriptional responses to infection, we can identify and characterize molecules critical for control of infection. To achieve this goal we will perform genome-wide characterization of gene expression profiles in differentially susceptible inbred mouse strains following infection with Listeria monocytogenes. To understand how changes in gene expression affect immune function, we have to differentiate between primary and secondary differences. Primary expression differences are caused by genetic polymorphisms at the gene locus itself, which directly affect the level of the gene transcript. Accordingly, secondary differences are those which reflect upstream functional or expression differences. We will use a novel Recombinant Inbred expression mapping approach to differentiate between primary and secondary changes in gene expression in mouse strains differentially susceptible to Listeria monocytogenes infection. Our pilot study will identify molecules differentially regulated in response to infection. Furthermore, it will allow us to refine our methodology for a future comprehensive study of changes in gene expression in differentially susceptible hosts over the course of the infectious disease. Identification of primary gene expression changes will lead to identification of genetic polymorphisms controlling gene expression. In addition, these primary expression differences will serve as starting points for building a multilayer map of transcriptional responses to infection. We hope to use this map to identify novel therapeutic targets for treatment of infectious diseases.

描述（由申请人提供）：哺乳动物宿主，从近交系小鼠品系到人类，对各种细菌感染表现出广泛的表型反应。在小鼠中引发这种差异反应的病原体之一是单核细胞增生李斯特菌，这是一种革兰氏阳性细菌，是食物中毒的常见来源。 先前的研究已经证实，免疫反应的差异通常是由基因控制的。免疫反应的差异可以使用各种读数来表征，从基因表达变化到疾病结果。 目前，基因表达数据是描述生物系统最全面的方式。 此外，基因表达值可直接用于遗传数量性状作图实验。 因此，通过监测对感染的差异转录反应，我们可以识别和表征对控制感染至关重要的分子。 为了实现这一目标，我们将对单核细胞增生李斯特菌感染后差异易感性近交小鼠品系的基因表达谱进行全基因组表征。 为了了解基因表达的变化如何影响免疫功能，我们必须区分主要差异和次要差异。 主要表达差异是由基因位点本身的遗传多态性引起的，它直接影响基因转录本的水平。 因此，次要差异是反映上游功能或表达差异的差异。 我们将使用一种新的重组近交表达作图方法来区分对单核细胞增多性李斯特菌感染具有不同敏感性的小鼠品系中基因表达的初级和次级变化。 我们的试点研究将确定针对感染反应进行差异调节的分子。 此外，它将使我们能够完善我们的方法，以便未来全面研究传染病过程中不同易感宿主的基因表达变化。 主要基因表达变化的鉴定将导致控制基因表达的遗传多态性的鉴定。 此外，这些主要表达差异将作为构建感染转录反应多层图谱的起点。 我们希望利用这张图来确定治疗传染病的新治疗靶点。